EP0526545A1 - Isoquinoline amides and esters as 5 ht3 receptor antagonists - Google Patents

Abstract

Isoquinoline derivatives (I) having 5-HT3 receptor antagonist efficacy, process for their preparation and use as pharmaceuticals. In formula (I), E represents NH or O, R1 represents hydrogen, halogen, alkyl, alkoxy, hydroxy or nitro; Z is an azacyclic or azabicyclic side chain, such as a group of formula (a), (b) or (c) where p is 1 or 2, q is 1 or 3, r is 1 to 3; R3 or R4 represents hydrogen or alkyl and y is a group -CH2-X-CH2- in which X represents -CH2-, oxygen, sulfur, or X is a bond; and (I) when the CO-EZ group is in position 1 and either R2 is in position 3 and represents hydrogen, alkyl or alkoxy, or R2 is in position 4 and represents hydrogen CF3, alkyl, acyl, phenyl (to substitution) of acylamino or amino (substituted), aminocarbonyl (substituted) or aminosulphonyl (substituted); (II) the group CO-E-Z is in position 3 and either R2 is in position 1 and represents hydrogen, alkyl or alkoxy or R2 is in position 4 and represents hydrogen or alkoxy.

Description

ISOQUINOLINE AMIDES AND ESTERS AS 5-HT₃

RECEPTOR ANTAGONISTS.

This invention relates to novel compounds having useful pharmacological properties, to pharmaceutical compositions containing them, to a process and intermediates for their preparation, and to their use as pharmaceuticals.

GB 2145416A (Sandoz Ltd) describes a group of naphthylene, chromene and quinoline derivatives with saturated

azabicyclic side chains, and having 5-HT₃ receptor

antagonist activity.

A class of structurally distinct compounds having an

isoquinoline moiety, has now been discovered. These

compounds have 5-HT₃ receptor antagonist activity.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein

E is NH or O,

R₁ is hydrogen, halogen, C _{1 -4} alkyl, C_1-4 alkoxy, hydroxy or nitro;

Z is an azacyclic or azabicyclic side chain, such as a group of formula (a), (b) or (c):

wherein

p is 1 or 2; q is 1 to 3; r is 1 to 3;

R₃ or R₄ is hydrogen or C_1-4 alkyl, and Y is a group

-CH₂-X-CH₂- wherein X is -CH₂-, oxygen, sulphur or X is a bond; and i) the group CO-E-Z is in the 1-position and either R₂ is in the 3-position and is hydrogen, C_{1 -6} alkyl or C_{1 -6} alkoxy, or R₂ is in the 4-position and is hydrogen, halogen, CF₃, C_{1 -6} alkyl, C_{1 -7} acyl, C_{1 -7} acylamino, phenyl optionally substituted by one or two C_{1 -6} alkyl, C_{1 -6} alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally

substituted by one or two C_{1 -6} alkyl or C_{3 -8}

cycloalkyl groups or by C_{4 -5} polymethylene or by phenyl, C_{1 -6} alkylsulphonyl, C_{1 -6} alkylsulphinyl, C_{1 -6} alkoxy, C_{1 -6} alkylthio, hydroxy or nitro; or ii) the group CO-E-Z is in the 3-position and either R₂ is in the 1-position and is hydrogen, C_{1 -6} alkyl or C_{1 -6} alkoxy, or R₂ is in the 4-pσsition and is hydrogen or C_{1 -6} alkoxy; having 5-HT₃ receptor antagonist activity.

Suitable examples of the group R₁ include hydrogen₇ bromo, chloro, methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl, methoxy, ethoxy, n- and iso-propoxy, and n-, iso-, sec- and tert-butoxy.

Suitable examples of Z are described in the art relating to 5-HT₃ receptor antagonists, ie. as follows: i) GB 2125398A (Sandoz Limited)

ii) GB 2152049A (Sandoz Limited)

iii) EP-A-215545 (Beecham Group p. I.e.)

iv) EP-A-214772 (Beecham Group p. I.e.)

v) EP-A-377967 (Beecham Group p. I.e.)

vi) EP-A-358903 (Dianippon Pharmaceutical Co. Ltd.)

Particular side chains of interest are depicted thus: Tropane

Granatane Oxa/thia-qranatane

Quinuclidine

Isoquinuclidine

Isogranatane

Oxa/thia-isoqranatane

Isotropane

wherein

R is hydrogen or methyl; and X is oxygen or sulphur. Side chains Z of particular interest include tropane and oxagranatane, where R is methyl.

E is preferably NH. When the group CO-E-Z is in the 1-position suitable examples of the group R₂ when in the 4-position, include the

following groups; hydrogen, chloro, bromo, methyl, ethyl, amino, methylamino, dimethylamino, phenyl, C_{1 -4}

alkanoylamino such as formylamino, acetylamino,

propionylamino, n- and iso-butyrylamino, aminosulphonyl, and amino and aminosulphonyl optionally substituted by one or two methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or

tert-butyl or phenyl groups; nitro, methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio, hydroxy, methylsulphonyl and ethylsulphonyl or when R₂ is in the 3-position suitable examples, include the following groups, hydrogen, methyl, ethyl, n- or iso-propyl, methoxy, and ethoxy.

When the group CO-E-Z is in the 3-position, suitable

examples of the group R₂ when in the 1-position, include the groups hydrogen, methyl, ethyl, n- or iso- propyl, methoxy and ethoxy, or when R₂ is in the 4-position, suitable examples include the following groups; hydrogen, methoxy and ethoxy.

Preferred R₂ groups, in any of the positions specified above, include hydrogen, methyl and methoxy. R₂ is

preferably in the 1-position. For the avoidance of doubt, all alkyl and alkyl containing moieties are straight chained or branched.

Examples of R₃/R₄ when alkyl are methyl, ethyl, n- and

iso-propyl, n-, iso-, sec- and tert-butyl, preferably methyl.

Preferably p, q and r are 1 or 2.

The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with

conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and

glucose-1-phosphoric acids. The pharmaceutically acceptable salts of the compounds of the formula (I) are usually acid addition salts with acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.

Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R_a-T wherein R_a is C_{1 -6} alkyl, phenyl-C_{1 -6} alkyl or C_{5 -7} cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R_a include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl, preferably methyl. Suitable examples of T include halide such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts of compounds of formula (I) also include internal salts such as

pharmaceutically acceptable N-oxides. The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable

solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.

It will of course be realised that some of the compounds of the formula (I) have chiral or prochiral centres and thus are capable of existing in a number of stereoisomeric forms including enantiomers. The invention extends to each of these stereoisomeric forms (including enantiomers), and to mixtures thereof (including racemates). The different stereoisomeric forms may be separated one from the other by the usual methods. It will also be realised that the isoquinoline nucleus in compounds of formula (I) may adopt an endo or exo

configuration with respect to Z. The endo configuration is preferred.

A group of compounds within formula (I) is of formula (II):

wherein the variables are as defined in formula (I).

Examples of the variables and preferred variables are as so described for corresponding variables in relation to formula (I).

A further group of compounds within formula (I) is of formula (III):

wherein q¹ is 1 or 2 and the remaining variables are as defined in formulae (I) and (II). Examples of the variables and preferred variables are as so described for the corresponding variables in formula (I).

There is a further group of compounds within formula (I) of formula (IV):

wherein r¹ is 1 or 2 and the remaining variables are as defined in formulae (I) and (II).

Examples of the variables and preferred variables are so described as the corresponding variables in formula (I).

The invention also provides a process for the preparation of a compound of formula (I) which process comprises reacting a compound of formula (V):

with a compound of formula A₂-Z ' wherein Z' is Z as defined in formula (I) wherein R₃ and R₄ are replaced by R₃' and R₄', A₁ and A₂ are moieties which react together to form an amide or ester linkage and R₃' and R₄' are R₃ and R₄

respectively, as defined in formula (I) or a

hydrogenolysable protecting group; and thereafter as desired or necessary, converting R₃', or R₄' when other than R₃ or R₄ respectively, to R₃ and R₄ respectively, and optionally forming a pharmaceutically acceptable salt of the compound of formula (I). Suitable values of A₁ and A₂ are, for example, as described in the aforementioned patent publications. For example, A₁ may be an actived carbonyl function such as an acid chloride or N-hydroxysuccinmide ester and A₂ may be an amino group, when E in formula (I) is NH.

Intermediates of the formula (V) are generally known or are prepared by analogous methods to those used for structurally related known compounds. Intermediates of formula A₂-Z' may be prepared from the corresponding exocyclic keto derivative of the azabicyclic side chain, prepared by condensation methods, often using a substituted piperidine, as described in the aforementioned patent references.

In a particular aspect, the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (VI):

with a compound of formula HJ-Z', or when J is oxygen, an active derivative thereof, wherein J is oxygen or NH, Q is a leaving group; R₃' and R₄' respectively is R₃ and R₄

respectively, as defined, or a hydrogenolysable protecting group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting R₃' or R₄', when other than R₃ or R₄, to R₃, or R₄ respectively, and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

Examples of leaving groups Q, displaceable by a nucleophile, include halogen such as chloro and bromo, C_1-4 alkoxy, such as CH₃O and C₂H₅O-, PhO-, or activated hydrocarbyloxy, such as Cl₅C₆O- or COQ forms a mixed anhydride, so that Q is carboxylic acyloxy.

If a group Q is a halide or COQ forms a mixed anhydride, then the reaction is preferably carried out at non-extreme temperatures in an inert non-hydroxylic solvent, such as benzene, dichloromethane, toluene, diethyl ether,

tetrahydrofuran (THF) or dimethylformamide (DMF). It is also preferably carried out in the presence of an acid acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or picoline, some of which can also function as the solvent. Alternatively, the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate. Temperatures of 0°-100°C, in particular 10-80°C are

suitable.

If a group Q is C_1-4 alkoxy, phenoxy or activated

hydrocarbyloxy, or activated ester, such as N- hydroxysuccinimide, then the reaction is preferably carried out in an inert polar solvent, such as toluene or

dimethylformamide. It is also preferred that the group Q is CI₃CO- and that the reaction is carried out in toluene at reflux temperature.

If a group Q is hydroxy, then the reaction is generally carried out in an inert non-hydroxylic solvent, such as dichloromethane, THF or DMF optionally in the presence of a dehydrating agent such as a carbodiimide, for example dicyclohexylcarbodiimide, optionally in the presence of N- hydroxysuccinimide. The reaction may be carried out at any non-extreme temperature, such as -10 to 100°C, for example, 0 to 80°C. Generally, higher reaction temperatures are employed with less active compounds whereas lower

temperatures are employed with the more active compounds.

If a group Q is carboxylic acyloxy, then the reaction is preferably carried in substantially the same manner as the reaction when Q₁ is halide. Suitable examples of acyloxy leaving groups include C_1-4 alkanoyloxy and C_{1 -4}

alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent, such as dichloromethane, at a non-extreme temperature for example ambient temperatures in the presence of an acid acceptor, such as triethylamine. C_{1 -4} alkoxycarbonyloxy leaving groups may be generated in situ by treatment of the corresponding compound wherein Q is hydroxy with a C_1-4 alkyl chloroformate.

If a group Q is activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as dimethylformamide. It is also preferred that the activated hydrocarbyloxy group is a pentachlorophenyl ester and that the reaction is carried out at ambient temperature.

When J is O the compound of formula HJ-Z', may be in the form of a reactive derivative thereof, which is often a salt, such as the lithium, sodium or potassium salt. R₃' and R₄' when other than R₃ and R₄ respectively, may be a hydrogenolysable protecting group which is benzyl optionally substituted by one or two groups selected from halo, C_1-4 alkoxy and C_{1 -4} alkyl. Such benzyl groups may, for example, be removed, by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (VII) or (VIII) respectively:

R

wherein the variables are as hereinbefore defined. This invention also provides a further process for the preparation of a compound of the formula (I) wherein Z is a) or c) or a pharmaceutically acceptable salt thereof, which comprises N-alkylating a compound of formula (VII) or (VIII) respectively, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I). In this further process of the invention 'N-alkylation' comprises the substitution of the N-atom depicted in formula (VII) or (VIII) respectively, by a group R₃ or R₄

respectively as hereinbefore defined. This may be achieved by reaction with a compound R₃Q₃ or R₄Q₃ as necessary wherein R₃ and R₄ are as hereinbefore defined and Q₃ is a leaving group.

Suitable values for Q₃ include groups displaced by

nucleophiles such as Cl, Br, I, OSO₂CH₃ or OSO₂C₆H₄pCH₃.

Favoured values for Q₃ include Cl, Br and I.

The reaction may be carried out under conventional

alkylation conditions, for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at non-extreme temperature such as at ambient or slightly above. Alternatively, 'N-alkylation' may be effected under

conventional reductive alkylation conditions.

Interconverting R₃ and R₄ respectively in the compound of the formula (VII), or (VIII) respectively, before coupling with the compound of the formula (VI) is also possible.

Such interconversions are effected conveniently under the above conditions. It is desirable to protect any amine function with a group readily removable by acidolysis such as a C_2-7 alkanoyl group, before R₃ or R₄ interconversions.

It is often convenient in the preparation of such a compound of formula (VII) or (VIII) to prepare the corresponding compound wherein the methylene group is replaced by -CO-, or for R₃ or R₄ is methyl, where the methyl group is replaced by alkoxycarbonyl. Such compounds may then be reduced using a strong reductant such as lithium aluminium hydride to the corresponding compound of formula (VII) or (VIII)

respectively.

The compounds of formula (VI) are known or are preparable analogously to, or routinely from, known isoquinoline compounds.

It will be realised that in the compounds of the formula (I) having a tropane, granatane or oxa/thia-granatane side chain, the -COE- linkage has an endo orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of endo and exo isomers of the compound of the formula (I) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the endo isomer may if desired by synthesised from the corresponding endo form of the compound of the formula (II). Corresponding

geometric isomeric pairs are possible for the

isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains.

Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally. The acid addition salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid.

The compounds of the present invention are 5-HT₃ receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders. Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain; emesis, includes in particular that of preventing vomiting and nausea associated with cancer therapy, and motion sickness. Examples of such cancer therapy include that using cytotoxic agents, such as cisplatin, doxorubicin and cyclophosphamide, particularly cisplatin; and also radiation treatment. CNS disorders include anxiety, psychosis, senile dementia and drug dependence. Gastrointestinal disorders include irritable bowel syndrome and diarrohea. 5-HT₃ receptor antagonists may also be of potential use in the treatment of obesity and/or arrhythmia.

The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid

preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional

excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch

derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be

presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,

emulsifying agents, for example lecithin, sorbitan

monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.

The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.

Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by

exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform

distribution of the compound of the invention. The invention further provides a method of treatment or prophylaxis of pain, emesis, CNS disorders and/or

gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the

compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.

However, a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.1 to 500mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of

approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.

No adverse toxicological effects are indicated at any of the aforementioned dosage ranges.

The invention also provides a pharmaceutical composition for use in the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders which

composition comprises an effect non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of pain, emesis, CNS disorders and/or

gastrointestinal disorders.

The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or

gastrointestinal disorders. The followinG Examples illustrate the preparation of

compounds of formula (I), the following descriptions

illustrate the preparation of intermediates. Description 1

4-Methyl-1-isoquinoline carboxaldehyde (D1) To a solution of 1,4-dimethyl isoquinoline (9.46g) (K.C. Agrawal, P.D. Mooney and A. C. Sartorelli, J. Med. Chem., 1976, 1 9, 970) in 1,4-dioxane (250 ml) was added selenium dioxide (6.65g) and the mixture heated under reflux, under an atmosphere of nitrogen, for 4h. After allowing the reaction mixture to cool to room temperature, the

precipitated selenium was removed by filtration and the filtrate concentrated to dryness. The residue was purified by flash chromatography on silica gel, using light petroleum ether (bp 60-80°C) and diethyl ether (up to 20% v/v) as eluent, to afford the aldehyde (D1) (3.78g) as a tan solid. Mp. 61-63°.

M.S. M⁺ 171

n.m.r. (CDCI₃, 250 MHz)

δ 2.74 (s. 3H)

7.71-7. .87 (m. 2H)

8.05 (d, 1H)

8.63 (s, 1H)

9.38 (d, 1H)

10.35 (s, 1H)

Description 2

4-Methyl-1-isoquinoline carboxylic acid (D2)

To an aqueous solution of silver oxide (prepared by the addition of silver nitrate (5g) in water (10 ml) to a stirred solution of sodium hydroxide (2.40g) in water (10 ml)) was added, at 0°C, 4-methyl-1-isoquinoline carboxaldehyde (D.1) (2.50g), in portions. The reaction mixture was stirred at ambient temperatures overnight. The silver suspension was removed by filtration and washed with hot water (3x5 ml). The combined filtrate and washings were acidified with cone. HCl and extracted with chloroform (3x50 ml). The organic phase was dried (MgSO₄) and concentrated in vacuo to afford the title compound (D2) (980 mg) as a beige solid mp. 155-57°. M.S. mr 188

n.m.r. (CDCI₃, 250 MHz)

δ 2.75 (s. 3H)

7.79-7 .92 (m, 2H)

8.07 (d, 1H)

8.43 (s, 1H)

9.67 (d, 1H)

10.58 (bs, 1H)

Example 1 endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)isoquinolin- 1-carboxamide (E1)

A solution of isoquinolin-1-carboxylic acid (2g),

N-hydroxysuccinimide (1.5g) and

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.6g). was stirred in dry DMF (50ml) at room temperature for 4 hours. The reaction mixture was cooled at 0°C,

endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (2g) in CH₂CI₂ (30ml) was added and the mixture stirred at room temperature overnight. The solvent was removed and the residue dissolved in CH₂CI₂, washed with saturated aqueous NaHCO₃ solution, dried and concentrated. The residue was recrystallised from Ethyl acetate and petrol (Bpt. range 60-80°C), to give the title compound (2.4g). m.p. 155-157°C.

Examples 2 to 6

The following compounds are prepared analogously to example 1 or as hereinbefore described.

Example 2 endo-N-(8-Methyl-8-azabicvclo[3.2.1]octan-3-yl)isoquinolin- 1-carboxamide (E2) mp 87- 88°

¹H-NMR . (CDCI₃)

δ 9.67 (d, 1H)

8.75 (d, 1H)

8.48 (d, 1H)

7.9-7.6 (m, 4H)

4.42-4.28 (m, 1H)

3.25 (brs, 2H)

2.42-1.70 (m, IIH including 2.35, s, 3H)

Example 3 endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)

isoguinolin-3-carboxamide (E3) mp 133-136°

¹H-NMR (CDCI₃)

δ 9.19 (s, 1H)

8.85 (brd, 1H)

8.60 (s, 1H)

8.10-7.95 (m, 2H)

7.80-7.65 (m, 2H)

4.36 (dt, 1H)

3.25 (brs, 2H)

2.44-1.95 (m, 9H including 2.36, s, 3H)

1.85 (brd, 2H) Example 4

N-(Quinuclidin-3-yl)isoquinolin-1-carboxamide(E4) mp 115-117°

¹H-NMR (CDCI₃)

δ 9.62 (d, 1h)

8.51-8.40 (m, 2h)

7.9-7.62 (m, 4h)

4.35-4.15 (m, 1h)

3.58-3.41 (m, 1h)

3.10-2.82 (m, 4h)

2.75 (dd, 1h)

2.41-1.5 (m, 5h)

Example 5 endo-N-(9-Methyl-9-aza-3-oxabicyclo[3.3.1]nonan-7-yl)- isoquinolin-1-carboxamide (E5) mp 148-150°

¹H-NMR (CDCI₃)

δ 10.03 (brd, 1H)

9.42 (d, 1H)

8.50 (d, 1H)

7.9-7.62 (m, 4H)

4.88-4.72 (m, 1H)

4.10 (d, 2H)

3.68 (d, 2H)

2.75 (brs, 2H)

2.67-2.50 (m, 5H including 2.60, s, 3H) 1.60 (d, 2H) Example 6 endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-methyl- 1-isoquinolin-1-carboxamide hydrochloride (E6) A solution of 4-methyl-1-isoquinoline carboxylic acid (500 mg) (D2) and N-hydroxy succinimide (368 mg) in dry DMF (15 ml) was stirred under an atmosphere of nitrogen at ambient temperatures for 30 min. 1-Ethyl-3-(3-dimethylaminopropyl)- carbodiimide (768 mg) was added in one portion and stirring continued for 1h. The reaction mixture was cooled to 0°C and a solution of endo-8-methyl-8-azabicyclo[3.2.1}octan-3- amine (374 mg) in DMF (5 ml) was added dropwise and stirring continued for 20h at ambient temperatures. The solvent was removed in vacuo and the residue partitioned between

chloroform (50 ml) and 10% aq. NaOH (5 ml). The organic phase was dried (MgSO₄) and evaporated under reduced

pressure. The residue was purified by flash chromatography on silica gel, using chloroform and ethanol (up to 10% v/v) as the eluent to afford an oil. Treatment with ethanolic HCl gave the title compound (200 mg) as a pale yellow solid, m.p. 140-43°.

M.S. M⁺ 309 (Free base)

1H-NMR (d₄-MeOH, 250 MHz)

δ 2.33-2.52 (m, 5H)

2.59-2.65 (m, 2H)

2.84 (s, 3H)

2.92 (s, 3H)

3.02 (d, 1H)

3.89-4.06 (m, 2H)

4.40-4.53 (m, 1H)

8.10 (t, 1H)

8.30 (t, 1H)

8.44-8.60 (m, 3H) 5-HT₃ Receptor Antagonist Activity

Compounds are evaluated for antagonism of the von

Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised rat according to the following method:

Male rats 250-350g, are anaesthetised with urethane

(1.25g/kg intraperitoneally) and blood pressure and heart rate are recorded as described by Fozard J.R. et al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980). A submaximal dose of 5-HT (usually 6μg/kg) is given repeatedly by the

intravenous route and changes in heart rate quantified.

Compounds are given intravenously and the concentration required to reduce the 5-HT-evoked response to 50% of the control response (ED₅₀) is then determined.

Claims

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein

E is NH or 0,

R₁ is hydrogen, halogen, C_1-4 alkyl, C_1-4 alkoxy, hydroxy or nitro;

Z is an azacyclic or azabicyclic side chain; and i) the group CO-E-Z is in the 1-position and either R₂ is in the 3-position and is hydrogen, C_{1 -6} alkyl or C_{1 -6} alkoxy, or R₂ is in the 4-position and is hydrogen, halogen, CF₃, C_{1 -6} alkyl, C_{1 -7} acyl, C_{1 -7} acylamino, phenyl optionally substituted by one or two C_{1 -6} alkyl, C_{1 -6} alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally

substituted by one or two C_{1 -6} alkyl or C_3-8

cycloalkyl groups or by C_{4 -5} polymethylene or by phenyl, C_{1 -6} alkylsulphonyl, C_{1 -6} alkylsulphinyl, C_{1 -6} alkoxy, C_{1 -6} alkylthio, hydroxy or nitro; or ii) the group CO-E-Z is in the 3-position and either R₂ is in the 1-position and is hydrogen, C_{1 -6} alkyl or C_{1 -6} alkoxy, or R₂ is in the 4-position and is hydrogen or C_{1 -6} alkoxy; having 5-HT₃ receptor antagonist activity.

2. A compound according to claim 1 wherein E is NH.

3. A compound according to claim 1 or 2 wherein CO-E-Z is in the 1-position.

4. A compound according to any one of claims 1 to 3 wherein R₁ is hydrogen.

5. A compound according to any one of claims 1 to 4 wherein Z is tropane, granatane, oxa/thia-granatane,

quinuclidine, isoquinuclidine, isogranatane, oxa/thia- isogranatane or isotropane.

6. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)iso- quinolin-1-carboxamide.

7. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)- isoquinolin-1-carboxamide.

8. endo-N-(8-Methyl-8-azabicvclo[3.2.1]octan-3-yl)- isoquinolin-3-carboxamide.

9. N-(Quinuclidin-3-yl)isoquinolin-1-carboxamide.

10. endo-N-(9-Methyl-9-aza-3-oxabicyclo[3.3.1]nonan-7-yl)- isoquinolin-1-carboxamide.

11. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4- methyl-1-isoquinolin-l-carboxamide.

12. A pharmaceutically acceptable salt of a compound according to any one of claims 6 to 11.

13. A compound according to claim 1 substantially as defined herein with reference to the Examples.

14. A process for the preparation of a compound according to claim 1, which process comprises reacting a compound of formula (V):

with a compound of formula A₂-Z' wherein Z' is Z as defined in claim 1 wherein R₃ and R₄ are replaced by R₃' and R₄', A₁ and A₂ are moieties which react together to form an amide or ester linkage and R₃' and R₄' are R₃ and R₄ respectively, as defined in claim 1, or a hydrogenolysable protecting group; and thereafter as desired or necessary, converting R₃', or R₄' when other than R₃ or R₄ respectively, to R₃ and R₄ respectively, and optionally forming a pharmaceutically acceptable salt of the compound of formula (I).

15. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

16. A method of treatment or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound according to claim 1.

17. A compound according to any one of claims 1 to 13 for use as an active therapeutic substance.

18. A compound according to any one of claims 1 to 13 for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders.

19. The use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders.